It has been estimated that 42 million people have thyroid disorders in India.[1] Among them, hypothyroidism is common, more so in women. It has been estimated that the prevalence of hypothyroidism is about 3.9% in India.[2] However, subclinical hypothyroidism is more common, about 8% in India, and this varies across several studies [Table 1].[3],[4],[5],[6]

The prevalence of subclinical hypothyroidism seems to be high in India. It has been estimated that about 88% of participants seemed to be taking iodized salt.[3] Hence, the etiology of subclinical hypothyroidism requires further study. The most common cause of subclinical hypothyroidism seems to be autoimmunity.[3],[4],[5],[6]

Testing for subclinical hypothyroidism is important from the Indian perspective. In India, there are many laboratories that screen for thyroid functions as part of their checkups and this is probably leading to greater case detection. However, all patients with subclinical hypothyroidism do not require treatment. Hence, there is a need to characterize the participants with subclinical hypothyroidism better.

In subclinical hypothyroidism, it is always good to repeat the tests in clinical practice to rule out an erroneous report or for confirmation. However, there is yet another reason to repeat tests after a period of time, and that is because, in a proportion of participants, spontaneous resolution of hypothyroidism can occur.[7],[8],[9]

In a recent study called the TRUST trial, conducted in elderly participants, nearly 6 out of every 10 eligible participants with a high thyroid-stimulating hormone (TSH) level returned to euthyroid level at the time they were assessed for entry into the study.[7] Other studies too reveal that certain participants with subclinical hypothyroidism can exhibit a spontaneous resolution of high TSH levels.[8],[9],[10]

A study by Meyerovitch et al. studied TSH testing and thyroid disease management pattern among primary care practitioners in the USA.[8] The study included 422,242 participants over a 5-year period. The results were intriguing. The results suggest that nearly 18% of the adult population had a thyroid function test. Moreover, the primary care physicians ordered 3.73 TSH tests per person over 5 years. More than 95% of these tests were normal. This clearly indicates that there is a heightened frequency of testing of TSH among primary care practitioners. This may accrue from the reality that subclinical hypothyroidism is nowadays suspected commonly by primary care physicians and that symptoms of subclinical hypothyroidism may be subtle or because the disease is often asymptomatic. However, there is certainly a need for better characterization of the disease, as argued in a recent publication by Taylor et al. in 2018.[9]

The study by Meyerovitch et al. also yielded fascinating insights into the natural history of participants with a high TSH.[8] Out of the 422,242 participants who had their TSH measured, 3.0% were elevated (>5.5 to ≤10 mIU/L) and 0.7% were highly elevated (>10 mIU/L). The follow-up results of these patients is instructive. For participants with elevated TSH level, 62% of these TSH values had become normal spontaneously without any levothyroxine therapy over a period of 5 years.

These reports are consistent with a study by Díez et al., who studied 107 patients older than 55 years.[10] About 37% of high TSH values resolved spontaneously. An initial baseline higher TSH predicted late resolution, and the majority of normalizers who resolve did so relatively early on, that is, within 18 months. However, in this study, only a minority of normalizers achieved a TSH below 2 mIU/L. Interestingly, antithyroid peroxidase (TPO) antibodies, which are well known to predict progression from subclinical to overt hypothyroidism, did not predict resolution from subclinical hypothyroidism to a euthyroid state. Not all experts agree, however. A manuscript by Huber et al. showed that only 3% of 82 patients with subclinical hypothyroidism (follow-up period: 9.2 years) have spontaneous resolution; in this group, however, about half of the patients were postthyroidectomy or postradioiodine therapy.[11] Ideally, such studies are best conducted in participants who are not known to have any thyroid disease. Two smaller studies by Parle et al. and Gussekloo et al. also show that 16%–50% of subclinical hypothyroidism may spontaneously resolve.[12],[13]

Clearly, the treatment of subclinical hypothyroidism is controversial.[14],[15],[16] These studies have clinical implications for the practicing doctor, with regard to nonpregnant adults. The natural history of subclinical hypothyroidism in pregnant women and children is another topic and beyond the scope of this editorial. However, with regard to the testing and treatment of subclinical hypothyroidism in nonpregnant adults, a few points are probably important. First, at least two thyroid function tests are needed for diagnosis. Obviously, a readership like ours will appreciate that thyroid function tests must be ordered after a thorough assessment of history, symptoms, and signs. If the thyroid function tests reveal subclinical hypothyroidism, progression to overt hypothyroidism is slow; only 2%–6% per year may progress within 5–6 years.[16] Only participants with TPO antibodies positive and with a TSH >10 mIU/L may progress faster. Hence, retesting every 6 weeks may not be necessary, except in the presence of compelling clinical indications, for example, in severely symptomatic participants or when the lady with subclinical hypothyroidism would like to plan pregnancy. In most other participants, in general, retesting a high TSH after 3–6 months may be sufficient. If, however, TSH levels remain elevated for 1–3 years or more, subclinical hypothyroidism could be considered long term and probably treated based on symptoms or rising TSH titer (TSH >10 mIU/L).

Periodic retesting of participants with normal thyroid functions may not be needed unless clinically indicated; it has been reported that more than 95% of biochemically euthyroid participants would continue to remain euthyroid over a period of 5 years. Given the ambiguity of the natural history of subclinical hypothyroidism, universal screening of the general population is quite unnecessary. Screening may, however, be appropriate for special populations such as women planning pregnancy, or with a goiter, or symptoms of hypothyroidism, participants with unexplained hyponatremia or hyperprolactinemia, dyslipidemia, or infertility. These subpopulations, if diagnosed with subclinical hypothyroidism, may benefit from its treatment with levothyroxine; a discussion of the indications for treatment and dosing considerations is beyond the scope of this brief editorial.

It is also important to speculate what lies ahead in the future. Current research seems to question the need for therapy of subclinical hypothyroidism in many subgroups. The benefits of treating subclinical hypothyroidism in older people remain controversial. While therapy of subclinical hypothyroidism can reduce dyslipidemia, improve endothelial function, and reduce cardiovascular risk, the role of therapy in reducing a composite end point of fatal and nonfatal myocardial infarction and stroke in a large randomized controlled study remains to be established. The cardiovascular outcome-related data for subclinical hypothyroidism need further research.[14] The effects of overt primary hypothyroidism on cognition and neuropsychological function are well known, but the effects of subclinical hypothyroidism on these parameters are open to question.[15] It is well known that treatment of subclinical hypothyroidism may push the TSH into a low, i.e., thyrotoxic range, causing subclinical hyperthyroidism.

However, it is possible that some patient groups may benefit from therapy and it is important to select the right patient who may benefit from therapy.[16] Twin studies have suggested that the TSH range may be genetically determined to an extent.[17] Genetic studies of variants of subclinical hypothyroidism which may help doctors choose the right patient who may benefit from treatment of subclinical hypothyroidism. Nongenetic factors could also play a role. As early as 1992, a manuscript by Takasu et al. described the follow-up of 21 participants with hypothyroidism who had associated TSH receptor-blocking antibodies.[18] Fifteen of these 21 participants, when followed up to 8 years, had spontaneous disappearance of the TSH receptor-blocking antibodies. When levothyroxine was discontinued in these 15 participants, 6 of these participants remained euthyroid and levothyroxine free when followed up to 2.1 years. Clearly biological factors including genetics, immunity, phenotype, and other factors may be important in “spontaneous” normalization of thyroid function; these aspects need further research.

Needless to say, an Indian-specific study of the realities of thyroid disease-related clinical practice, follow-up of cases of subclinical hypothyroidism, and prediction of those at higher likelihood of spontaneous resolution may help the medical community to more precisely treat subclinical hypothyroidism.